Is MYO7A p.Val408Leu (c.1222G>C) pathogenic?

MYO7A p.Val408Leu (c.1222G>C) is classified Uncertain significance in MYO7A (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-01). AlphaMissense: ambiguous (0.3437); Ultra-rare (popmax 0.0111%, sas).

How common is MYO7A p.Val408Leu (c.1222G>C) in the general population?

MYO7A p.Val408Leu (c.1222G>C) is ultra-rare (popmax 0.0111%, sas) (gnomAD).

What do computational predictors say about MYO7A p.Val408Leu (c.1222G>C)?

AlphaMissense predicts ambiguous (score 0.3437) — an in-silico prediction, not a clinical call.

MYO7A p.Val408Leu

c.1222G>C · rs782797465 · VCV1990144

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3437 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, sas)

Computational evidence

Protein change
AlphaMissense	0.3437	ambiguous
REVEL	0.359	indeterminate
SaProt	LLR -6.15	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP -2.1, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic
Overall
CADD	24.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0111% South Asian · 10/89,924 alleles

Filtering AF 0.00601% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00458%

Overall 0.000683% 11/1,609,492 alleles · ultra-rare exomes 10/1,457,434 · genomes 1/152,058 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0111%	8,992
European (non-Finnish)	8.49e-05%	1,178,178

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: MYO7A
Protein: p.Val408Leu
Coding: c.1222G>C
MANE Select: NM_000260
dbSNP: rs782797465
Type: single nucleotide variant
Location: chr11:77160994 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 408: the myosin motor domain

Full MYO7A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MYO7A p.Val408Met Uncertain significance ★★ ⚠ same residue
MYO7A p.Ala1288Pro Likely pathogenic ★★★ same type
MYO7A p.Arg1168Gln Pathogenic ★★★ ⚠ same type
MYO7A p.Arg1873Gln Pathogenic ★★★ ⚠ same type
MYO7A p.Arg395Cys Likely pathogenic ★★★ ⚠ same type
MYO7A p.Arg668Cys Pathogenic ★★★ same type
MYO7A p.Arg853His Likely pathogenic ★★★ same type
MYO7A p.Glu968Asp Likely pathogenic ★★★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/myo7a-p-val408leu (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown